Are You Confident of the Diagnosis?

What you should be alert for in the history

Werner syndrome (WS) is a type of progeroid syndrome characterized by the development of premature aging. It is often referred to as progeria of adults with average age of diagnosis in the 30’s.

Characteristic findings on physical examination

On physical exam, patients have a characteristic short stature, stocky trunk, slender extremities, a mask-like face, micrognathia, a bird-like nose, and high-pitched voices secondary to laryngeal atrophy. Other characteristic findings include an altered distribution of subcutaneous fat, trophic ulcers of the feet and over other bony prominences, hypermelanosis, soft tissue calcifications, and atrophy of the extremities.

Historically, patients have a life expectancy of approximately 47 years, and develop signs of aging including skin wrinkling, graying of the hair, alopecia, and cataracts at an early age. Growth retardation is generally noticeable at the time of puberty. Sclerodermoid and poikilodermatous hyperpigmentation changes are seen throughout the body, with the former being responsible for the mask-like faces or bird-like nose phenotype.

Expected results of diagnostic studies

The initial work-up for a patient suspected of having WS should include a thorough history (including a detailed discussion of family history) and physical exam. Cataracts, skin changes, short stature, and graying or loss of hair are the four signs seen in more than 95% of diagnosed cases. Preliminary laboratory studies to obtain include a complete blood count, a complete metabolic panel (including liver and lipid studies), thyroid studies (TSH), and fasting blood glucose.

The formal diagnosis of WS relies on cytogenetic and genomic molecular analysis consisting of nucleotide sequencing with Western blot analysis. A helpful marker of the disease is an elevated urinary hyaluronic acid. A skin biopsy may be performed to help clarify the diagnosis, however the site of biopsy should never be on the lower extremities as these are prone to nonhealing ulcerations.

In WS patients with scleroderma-like skin, the main histological changes are (1) replacement of the subcutaneous tissue by hyalinized connective tissue, (2) hyalinized connective tissue in the lower dermis, and (3) hyalinization and formation of aneurysms in the dermal blood vessels. Radiological findings of WS patients include osteoarthritis, osteosclerosis of the phalanges, calcifications of the soft tissues of the extremities, blood vessels, and cardiac valves.

Diagnosis confirmation

Other premature aging syndromes are on the differential diagnosis of WS including Hutchinson-Gilford progeria syndrome, Cockayne syndrome, ataxia-telangiectasia, Rothmund-Thomson syndrome and mandibuloacral dysplasia.

WS can be distinguished from Hutchinson-Gilford progeria syndrome by its later onset, presence of cataracts, hypogonadism, laryngeal atrophy, and osteosclerosis of the distal extremities. Cockayne Syndrome is distinguished from WS by its characteristic neurological degeneration (optic atrophy, deafness, nervous system demyelination).

Ataxia-telangiectasia is characterized by telangiectasias of the bulbar conjunctivae, cheeks, nose and ears, cafe-au-lait macules, cerebellar ataxia, nystagmus, and recurrent sinopulmonary infections. Mandibuloacral dysplasia presents very similarly to WS but its characteristic facial features (beaked nose, small recessed chin) and absence of bilateral cataracts differentiates it from WS. Finally, Rothmund-Thomson syndrome patients may display progeroid features but differs from WS in that it is a childhood onset disorder wth distinctive cutaneous features consisting of telangiectasias, poikiloderma, and scaling.

Other differential diagnoses for WS to consider includes scleroderma. The absence of premature atherosclerosis and cataracts, the presence of Raynaud’s phenomenon, and positive auto-antibodies favor a diagnosis of systemic scleroderma over WS. In addition, the loss of connective tissue and fat in WS causes the the skin to be bound tightly to the underlying tissues and around joints causing an inability to pinch or lift the skin up. This contrasts to scleroderma, in which pinching of the skin is possible early in the course of disease

Who is at Risk for Developing this Disease?

WS is a rare autosomal recessive disorder with a frequency ranging of approximately 1:59,000 in North Sardinia, 1:100,000 in Japan, and 1:1,000,000 - 1:10,000,000 worldwide. It affects males and females with equal frequency and has been described in all races.

The high frequency of cases in North Sardinia are related to a cluster of cases traced to a single family group composed of several consanguineous marriages. The majority of Japanese WS patients reported in the literature were also born from consanguineous marriages. It is estimated that as many as 1:180 Japanese citizens carries the WS gene mutation.

What is the Cause of the Disease?

Etiology

Pathophysiology

A mutation or deletion in the Werner (WRN) gene located on chromosome 8p12 is implicated in patients diagnosed with WS. Many mutations (more than 50) have been detected and described, and despite these molecular distinctions, the clinical features of patients affected by WS are strikingly similar worldwide.

The WRN gene encodes a homolog of the E. coli Rec Q DNA helicase (RECQL2), which functions in DNA repair and integrity; it has ATPase, helicase, exonuclease and single-stranded DNA annealing activities. A majority of mutations result in a truncated WRN protein that lacks the nuclear localization signal, thus it appears that the inability of WRN to be transported into the nucleus is a critical aspect in the pathogenesis of WS.

Extensive studies have shown that WS cells have telomere shortening, frequent telomere fusions, and chromosomal rearrangements. Therefore, the mutations in the WRN gene appear to contribute to the instability of chromosomes in the cells of patients with WS.

Systemic Implications and Complications

Patients with WS are at an increased risk of developing many of the disease entities seen in the elderly at a premature age such as Type II diabetes mellitus, atherosclerosis, heart disease, osteoporosis, cataracts, and malignancies (particularly sarcomas and other connective tissue tumors). However, a high frequency of other malignancies including thyroid cancer, melanoma, and hematological cancers occur in this specific patient population as well.

Furthermore, these malignancies can occur in unusual sites. Melanomas of the acral lentiginous type can develop in the mucosas and are unrelated to sun exposure, while osteosarcomas in WS patients tend to be found in the lower extremities as opposed to the upper extremities in the general population.

Cardiovascular disease, cerebrovascular disease, and malignancy remain the most common causes of death in WS patients. Therefore these patients must be followed very closely by a multidisciplinary team including but not limited to primary care physicians, dermatologists, ophthalmologists, cardiologists, and endocrinologists. Routine screening with annual fasting blood glucose, basic metabolic panel, and cholesterol panel are appropriate measures. Annual ophthalmological exams are also prudent to screen for cataracts, which develop in the early 20’s to 30’s.

The severe and premature atherosclerosis associated with WS is also responsible for the frequent occurrence of non-healing extremity ulcers found in WS patients. Overtime, dystrophic soft tissue calcification and osteomyelitis can complicate these chronic ulcers. The extensive blood vessel calcifications decrease blood supply to the extremities, eventually leading to ischemia and gangrene. Therefore, amputations are common in older WS patients and account for a high degree of morbidity in this patient population.

Routine thorough physical exams and laboratory evaluation as necessary, early colon cancer screening and breast cancer screening may be warranted but specific guidelines are lacking for patients with Werner syndrome, given the paucity of evidence. Perhaps these screening exams need to be performed more frequently than in the normal population.

Soft Tissue Calcifications

Bisphosphonates (especially etidronate 20mg/kg daily)

Optimal Therapeutic Approach for this Disease

Currently, no cure exists for WS. The cornerstone of management is preventing the complications associated with the disease (see Table I). Emphasize smoking avoidance/cessation, a healthy diet along with regular exercise to WS patients, since such measures will help slow down the progression of atherosclerosis, heart disease, and diabetes. Exercise that incorporates resistance training is imperative to help prevent or slow down the development of osteoporosis.

Routine laboratory studies on at least an annual basis should screen for hyperlipidemia, diabetes, and thyroid dysfunction. A baseline DEXA scan to assess for bone mineral density at the time of diagnosis is also recommended for WS patients. Once an abnormality is discovered, treatment should not be delayed, and referral to specialty care should be made. For diabetics, strict control of blood sugar is necessary; one case reported in the literature illustrated the benefit of pioglitazone in a WS patient by ameliorating the impaired insulin sensitivity, hyperlipidemia and glycemic control in the patient.

WS patients universally develop premature cataracts (one study found that 87 out of 87 patients with a molecular confirmed diagnosis of WS developed cataracts). Therefore all WS patients should be monitored closely by ophthalmologists.

Patients should also be routinely followed for systemic signs of malignancy such as weight loss, night sweats, etc. Routine physical exams should be thorough and include inspection of the skin for suspicious lesions (with particular attention to the nail beds and soles of the feet for acral lentiginous melanomas), palpation of the thyroid for nodules, palpation of cervical, axillary, and femoral lymph nodes, and palpation of the abdomen to assess for hepatosplenomegaly and other abdominal masses.

Any abnormality on history and physical exam suggestive of malignancy warrants further laboratory investigation including but not limited to imaging, biopsy and referral to oncology. The utility of early screening has not been studied extensively but makes clinical sense for many WS patients.

The management of chronic leg ulcers, which account for a high degree of morbidity in WS patients, should focus on prevention. First, there must be strict control of the patient’s diabetes because this can contribute to the development of leg ulcers. Teach patients to keep the skin of the lower extremities clean and moisturized. Any activity that increases the risk of injury to the lower extremities should be avoided. Patients should wear protective, light pants that are not too tight. Any ulcer or wounds should be carefully managed by wound care specialists. Teach patients the signs of infection at an ulcer site such as the presence of warmth, pain, and fever. In severe cases, skin grafting may be necessary.

For painful soft tissue calcifications, several published cases have reported the use of etidronate in ameliorating pain symptoms.

Finally, inhibitors of p38 mitogen-activated protein kinase (MAPK) show promise as a possible therapeutic modality. In vitro studies have found that these experimental compounds help slow down and even reverse the aging process of WS fibroblast cells.

Patient Management

Explain to patients the natural course of WS and that no cure currently exists. However, emphasize that many of the complications seen in WS patients can be managed with a combination of periodic physical exams, laboratory monitoring, and lifestyle modifications such as smoking cessation, eating a well-balanced diet low in saturated fat and exercising on a daily basis.

Patients should learn about the different systemic complications associated with WS such as atherosclerosis, diabetes, osteoporosis, malignancies, leg ulcers and cataracts. In addition, the signs, symptoms, and ways to prevent each should be discussed thoroughly with the patient.

Genetic counseling should be provided to all families affected to ensure early identification and management of syndrome-related complications. Screening consisting of genetic analysis or prenatal diagnosis can also be implemented when the need arises. Importantly, family members who are heterozygotes have higher rates of malignancy and develop more cardiovascular events as compared to the normal population. Therefore, special attention is needed for cancer and heart disease surveillance in relatives of WS patients.

Teach patients to keep the skin of the lower extremities clean, dry and moisturized. Any activity that increases the risk of injury to the lower extremities should be avoided. Patients should wear protective, light pants that are not too tight.

Finally, encourage patients to visit the International Registry of WS established by the Department of Pathology, University of Washington, Seattle, WA at http://www.wernersyndrome.org.

Unusual Clinical Scenarios to Consider in Patient Management

The key to Werner Syndrome is early recognition, genetic counseling, and prevention efforts for systemic complications. Although, many mutations exist for the WRN gene, the phenotypes of all patients are strikingly similar. A careful history and physical exam, along with knowledge of the premature aging syndromes, will help identify most patients with the disease.

An atypical variant of WS exists, in which patients develop an earlier onset of disease (early 20’s) with more severe symptoms and an accelerated progression rate. This subset of patients has a heterozygous missense mutation in the LMNA gene rather than the RECQL2 gene mutation. The absence of diabetes and bilateral cataracts are common in the atypical variant.

What is the Evidence?

(This article emphasizes Werner's syndrome as an important part of the differential in patients who present with scleroderma-like skin changes. An excellent discussion of the distinguishing features that separate systemic scleroderma from WS is also presented.)

(An overview of the premature aging syndromes is presented with a detailed discussion of both Hutchinson-Gilford progeria syndrome and Werner syndrome, their pathogenesis, clinical features and management.)

(A discussion of halting the accelerated aging process of fibroblasts in WS patients with the use of p38 MAP kinase inhibitors is presented, and suggested as a possible future therapeutic modality for WS patients.)

(The authors reported the benefit of administering etidronate, a bisphosphanate, in not only improving the clinical symptoms of a patient with Werner syndrome suffering from soft tissue calcifications, but also in reversing the calcifications.)

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